Etanercept formulations stabilized with xylitol

Abstract

The invention provides stabilized aqueous pharmaceutical etanercept compositions suitable for long-term storage of etanercept, methods of manufacture of these compositions, methods of administration, and kits containing same.

1 . A method of treating a subject in need of treatment for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Wegener's disease (granulomatosis), Crohn's disease (or inflammatory bowel disease), chronic obstructive pulmonary disease (COPD), Hepatitis C, endometriosis, asthma, cachexia, psoriasis, or atopic dermatitis comprising administering to the subject an aqueous etanercept composition comprising 25 to 75 mg/ml etanercept and 6 to 10 wt. % xylitol having a pH of about 6.0 to 6.6 or a pH within 10 percent of 6.0 and 6.6, wherein the composition is free or essentially free of arginine. 
     
     
         2 . The method of  claim 1 , comprising administering 10 to 100 mg etanercept per dose to the subject. 
     
     
         3 . The method of  claim 1 , comprising injecting the subject with the aqueous etanercept composition subcutaneously or intramuscularly. 
     
     
         4 . The method of  claim 1 , wherein the aqueous etanercept composition further comprises a buffer, a tonicity modifier, an excipient, or a combination thereof. 
     
     
         5 . The method of  claim 1 , wherein the aqueous etanercept composition comprises 50 mg/ml or a concentration within 10 percent of 50 mg/ml of etanercept. 
     
     
         6 . The method of  claim 1 , wherein the aqueous etanercept composition comprises meglumine, mannosylglycerate, mannosyllactate, mannosylglycolate, diglycerolphosphate, or a combination thereof. 
     
     
         7 . The method of  claim 1 , wherein the aqueous etanercept composition has osmolality of 180 to 420 milliosmoles. 
     
     
         8 . The method of  claim 1 , wherein the aqueous etanercept composition further comprises sodium phosphate, NaCl, sucrose, or a combination thereof. 
     
     
         9 . The method of  claim 1 , wherein the aqueous etanercept composition further comprises 1-100 mM NaCl, 1 to 5 wt. % sucrose, 1-5 wt. % meglumine, or a combination thereof. 
     
     
         10 . The method of  claim 1 , wherein the aqueous etanercept composition has no more than 10,000 particles per ml having a size greater than 5 μm. 
     
     
         11 . The method of  claim 1 , wherein the aqueous etanercept composition has monomer content greater than 90% as characterized by SEC (size exclusion chromatography) analysis at T 2 . 
     
     
         12 . The method of  claim 1 , wherein the aqueous etanercept composition is characterized by at least one of:
 (a) SEC (Size Exclusion Chromatography) analysis at T 2  of monomer content greater than 80 or 90%; aggregates content of less than 3 wt. %; and fragment 3 content less than 6 wt. %;   (b) HIC (Hydrophobic Interaction Chromatography) analysis at T 2  wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 3 wt. %; the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt. %; and the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt. %.   
     
     
         13 . The method of  claim 12 , wherein the aqueous etanercept composition has an HIC analysis at T 2  wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 1 wt. %; the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 95 wt. %; and the amount of the composition represented by peak 3 of the HIC chromatogram is less than 3 wt. %. 
     
     
         14 . The method of  claim 1 , wherein the aqueous etanercept composition is characterized by an SEC (Size Exclusion Chromatography) analysis at T 2  of greater than 80 wt. % monomer content; less than 3 wt. % aggregates content; and less than 6 wt. % fragment 3 content. 
     
     
         15 . The method of  claim 1 , wherein the aqueous etanercept composition is administered weekly or biweekly. 
     
     
         16 . The method of  claim 15 , wherein the aqueous etanercept composition is administered subcutaneously. 
     
     
         17 . The method of  claim 1 , wherein the aqueous etanercept composition is administered using a syringe or an injector pen. 
     
     
         18 . The method of  claim 17 , wherein the aqueous etanercept composition is administered subcutaneously. 
     
     
         19 . The method of  claim 1 , comprising administering 25 to 100 mg etanercept per dose to the subject.